The synthesis of a, b-oligodooxyribonucleotides with alternating (3'to 3')- and (5' to 5')- internucleotidic phosphodiester linkages (24 mers) complementary to a region overlapping the splice acceptor site of the second exon that encodes the HIV-1 tat gene product has been accomplished and the physicochemical properties of these analogues have been evaluated.Presumably because of the unnatural (3' to 3')- and (5' to 5')- phosphodiester linkages of a, b- oligonucleotides, these oligomers were considerably more resistant to endo- and exonucleases than unmodified b- oligonucleotides. Furthermore, a, b-oligonucleotides formed sequence specific complexes with complementary unmodified b-DNA oligomers which were as stable as those formed with b-oligodeoxynucleoside phosphorothioates but less stable than those composed of natural DNA strands under similar conditions. The stoichiometry of complexes composed of a, b-oligonucleotides and complementary b- oligodeoxyribonucleotides was determined as 1:1.a, b-Oligonucleotides formed also complexes with complementary oligoribonucleotides but with much lower affinity than with complementary b-DNA oligomers. It would appear, based on CD spectroscopy data, that a, b- oligodeoxyribonucleotides do not accomodate well the A-type helicity conferred upon hybridization with complementary RNA oligonucleotides. A greater flexibility of the a-nucleotidic residues of a, b- oligodeoxyribonucleotides may be required to bettter accommodate the A- type helicity of RNA . a-Nucleosides with nucleobases linked to the carbohydrate moieties through flexible arms are currently being synthesized in the laboratory along with novel acyclic nucleoside analogues in an effort to develop more potent antisense oligonucleotides targeted against HIV-1 mRNAs.